Preparation of 2-(2-arylmorpholin-2-yl) ethanol derivatives and intermediates

ABSTRACT

The invention relates to a process for the preparation of substituted 2-vinyl-2-arylmorpholine derivatives as described herein. This invention also relates to 2-vinyl-2-arylmorpholine derivatives as well as intermediates therefor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/370,399,filed Mar. 8, 2006, now allowed; which is a division of U.S. applicationSer. No. 10/030,600, filed Apr. 01, 2002, now U.S. Pat. No. 7,038,044B1, issued, May 2, 2006; which is a National Stage entry under 35 U.S.C.§ 371 of International application No. PCT/FR00/01,966, filed Jul. 07,2000, all of which are incorporated herein by reference in theirentirety; which claims the benefit of priority to French PatentApplication No. 99/09,061, filed Jul. 9, 1999.

A subject matter of the present invention is novel processes for thepreparation of substituted 2-(2-arylmorpholin-2-yl)ethanol derivativesin the enantiomerically pure form and intermediate compounds of use inthese processes.

Substituted 2-(2-arylmorpholin-2-yl)ethanol derivatives of formula:

in which X represents a halogen atom and * indicates the position of theasymmetric carbon atom, are key intermediates in the preparation oftachykinin receptor antagonist compounds, such as those disclosed ininternational application WO 96/23787 and in application EP-A-776 893.Thus, for example,(R)-(+)-3-{1-[2-(4-benzoyl-2-(3,4-difluorophenyl)morpholin-2-yl)ethyl]-4-phenylpiperidin-4-yl}-1,1-dimethylureais described as a powerful and selective antagonist for human NK₂receptors of neurokinin A (X. Emonds-Alt et al., Neuropeptides, 1997, 31(5), 449-458) and, consequently, may be of use in particular in thetreatment of conditions of the respiratory, gastrointestinal, urinary,immune or cardiovascular system, and of the central nervous system, andof pain and migraine.

The term “halogen atom” is understood to mean a bromine, chlorine,fluorine or iodine atom.

Preferably, a subject matter of the present invention is novel processesfor the preparation of enantiomerically pure compounds of formula (I) inwhich X represents a chlorine atom or a fluorine atom.

The preparation of compounds of formula (I) is illustrated ininternational application WO 96/23787 and is carried out according toscheme 1 below, in which X represents a halogen atom.

However, this process has disadvantages which are sufficient to excludeit from any use on an industrial scale.

For example, the compound of formula (I) in which X represents afluorine atom prepared by this process is obtained with a very lowyield, of the order of 1 to 2% calculated from the starting benzaldehydederivative, from the description of application WO 96/23787.

The compound of formula (I) in which X represents a chlorine or fluorineatom can also be prepared according to the enantioselective processdescribed in Tetrahedron: Asymmetry, 1998, 9, 3251-3262. However, thisprocess has the disadvantage of using starting materials, such asdiketene, and reagents, such asdichlorobis(triphenylphosphine)-palladium(II), AD-mix-β® or diethylazodicarboxylate, the costs of which render the production of compoundof formula (I) highly expensive on an industrial scale.

Novel processes for the preparation of the enantiomerically purecompound of formula (I) from simple starting materials and reagents andwith yields of the order of 5 to 25% have now been found.

Thus, according to one of its aspects, a subject matter of the presentinvention is a process A for the preparation of a compound, in theenantiomerically pure form, of formula:

in which X represents a halogen atom, of its salts with inorganic ororganic acids or of its salts with optically active organic acids,characterized in that:

a) a compound, in the racemic form, in the form of a mixture ofdiastereoisomers or in the enantiomerically pure form, of formula:

in which X is as defined for a compound of formula (I) and R₁ representsan N-protecting group chosen from a benzyl group, a benzyloxycarbonylgroup, a 1-chloroethyloxycarbonyl group, a tert-butyloxycarbonyl groupor an α-methylbenzyl group, is converted to a compound, in the racemicform, in the form of a mixture of diastereoisomers or in theenantiomerically pure form, of formula:

b) the compound of formula (III) thus obtained is deprotected;

c) if appropriate, when the compound of formula (I) thus obtained is inthe racemic form, the enantiomers are separated, and, optionally, theenantiomerically pure compound of formula (I) is converted to one of itssalts with inorganic or organic acids.

Preferably, in process A, R₁ represents a benzyl group or abenzyloxycarbonyl group.

When X represents a chlorine atom, preferably, in process A, R₁represents a tert-butyloxycarbonyl group or a 1-chloroethyloxycarbonylgroup.

When, in process A according to the invention, non-racemizing reactionswhich retain the chirality are used in stages a) and b), anenantiomerically pure compound of formula (I) is prepared directlyusing, as starting compound, an enantiomerically pure compound offormula (II).

In stage a) of process A, a compound of formula (II) is converted to acompound of formula (III) according to conventional methods well knownto a person skilled in the art.

Preferably, in stage a), the compound of formula (II) is first subjectedto a hydroboration reaction and then to an oxidation reaction to obtaina compound of formula (III).

The hydroboration reaction of an asymmetric alkene of formula (II) andthen the in situ oxidation reaction of the organoborane formed as anintermediate to give the primary alcohol of formula (III) are carriedout according to conventional methods, such as those described in J. Am.Chem. Soc., 1974, 96 (25), 7765-7770 or in J. Am. Chem. Soc., 1960, 82,4708-4712.

The hydroboration agents used, which are well known to a person skilledin the art, are, for example, either borane complexes, such as theborane-tetrahydrofuran complex or the borane-dimethyl sulfide complex,or 9-borabicyclo[3.3.1]nonane or 9-BBN. The borane used can also begenerated in situ, according to conventional methods, from, for example,sodium borohydride or lithium borohydride and an acid, such as a Lewisacid.

Use is preferably made of the borane-tetrahydrofuran complex,9-borabicyclo[3.3.l]nonane or the borane generated in situ by reactionof trimethylsilyl chloride with sodium borohydride.

When the borane-tetrahydrofuran complex is used, the latter participatesin the reaction in a proportion of 0.3 to 1.5 molar equivalents permolar equivalent of compound of formula (II).

When 9-borabicyclo[3.3.l]nonane is used, the latter participates in thereaction in a proportion of 1 to 1.5 molar equivalents per molarequivalent of compound of formula (II).

When the borane is generated in situ by reaction of trimethylsilylchloride with sodium borohydride, these compounds are each used in aproportion of 3 to 5 molar equivalents per molar equivalent of compoundof formula (II).

The hydroboration reaction is carried out in an inert solvent, such asan ether, for example diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether, or such as anaromatic hydrocarbon, for example toluene or xylene, at a temperature ofbetween ambient temperature and the reflux temperature of the solventand for a time of between 5 and 48 hours.

The organoborane formed as an intermediate substance is subsequentlysubjected to a conventional oxidation reaction. Preferably, theoxidation reaction is carried out under phase transfer catalysisconditions using a peroxide, in the presence of a strong base and of aphase transfer catalyst in an inert solvent and water.

It is preferable to use hydrogen peroxide as peroxide. Hydrogen peroxideparticipates in the reaction in a proportion of 3 to 5 molar equivalentsper molar equivalent of compound of formula (II).

The base used during the reaction is chosen from an alkali metalhydroxide, such as sodium hydroxide. It participates in the reaction ina proportion of 1 to 2 molar equivalents per molar equivalent ofcompound of formula (II).

The phase transfer catalyst is chosen from substituted quaternaryammonium salts, such as tetrabutylammonium hydrogensulfate. Itparticipates in the reaction in a proportion of 0.01 to 0.1 molarequivalent per molar equivalent of compound of formula (II).

The oxidation reaction is carried out in one of the solventsabovementioned above for the hydroboration reaction and at a temperatureof between 0° C. and 60° C.

This oxidation reaction is highly exothermic and requires control of theflow rate for introduction of the peroxide and of the temperature of thereaction medium.

The reaction takes place over a time of between the duration ofintroduction of the hydrogen peroxide solution and 48 hours.

As the hydrogen peroxide/tetrahydrofuran mixture is regarded asdangerous at the industrial stage, it is preferable to carry out theoxidation reaction in an aromatic solvent, preferably toluene. In thiscase, an exchange of solvent may be necessary before the oxidationreaction or, preferably, before the hydroboration reaction.

In stage b) of process A, the compound of formula (III) thus obtained isdeprotected according to conventional methods.

Thus, the deprotection of the benzyl group of the compound of formula(IIIa), the deprotection of the benzyloxycarbonyl group of the compoundof formula (IIIb) or the deprotection of the α-methylbenzyl group of thecompound of formula (IIIe) is carried out by hydrogenolysis, preferablyby catalytic hydrogenation, or by hydrogen transfer catalysis.

The catalytic hydrogenation is carried out in an inert solvent, such asan alcohol (methanol, ethanol or propan-2-ol, for example), an aromatichydrocarbon (toluene or xylene, for example) or an ester (ethyl acetate,for example), or in a mixture of these abovementioned solvents, in thepresence of a catalyst, such as palladium-on-charcoal or Raney nickel,under a pressure of between 1 and 10 bar, at a temperature of between 0°C. and 100° C. and for a time of between 1 and 24 hours.

The hydrogen transfer catalysis is carried out using ammonium formate inthe presence of a catalyst, such a palladium-on-charcoal, in an inertsolvent, such as an alcohol (methanol or ethanol, for example), at atemperature of between ambient temperature and the reflux temperature ofthe solvent and for a time of between 2 and 48 hours.

The deprotection of the 1-chloroethyloxycarbonyl group of the compoundof formula (IIIc) is carried out by reaction with methanol at atemperature of between ambient temperature and the reflux temperature ofthe solvent.

The deprotection of the tert-butyloxycarbonyl group of the compound offormula (IIId) is carried out by acid hydrolysis by means ofhydrochloric acid or trifluoroacetic acid, for example, in an inertsolvent, such as an alcohol (methanol or ethanol, for example), an ether(diethyl ether, dioxane or tetrahydrofuran, for example) or ahalogenated hydrocarbon (dichloromethane, for example), and at atemperature of between −10° C. and the reflux temperature of thesolvent.

When the compound of formula (I) is obtained in the racemic form, theenantiomers are separated in stage c) according to known methods.Preferably, the separation is carried out by preparation of an opticallyactive salt, by the action of an optically active organic acid, such asL-(+)- or D-(−)-mandelic acid, L-(−)- or D-(+)-di-para-toluoyltartaricacid, L-(+)- or D-(−)-tartaric acid, L-(−)- or D-(+)-dibenzoyltartaricacid or (1R)-(−)- or (1S)-(+)-10-camphorsulfonic acid, and thenseparation of the isomers, for example by crystallization. The desiredenantiomer is released from its salt in basic medium.

Preferably, the separation of the enantiomers of the compound of formula(I) is carried out by formation of an optically active salt, by theaction of L-(−)- or D-(+)-di-para-toluoyltartaric acid.

The enantiomerically pure compounds of formula (I) in the form ofoptically active salts with optically active organic acids are novel andform part of the invention.

The enantiomerically pure compounds of formula (I) in the form ofoptically active salts with optically active organic acids in which Xrepresents a chlorine atom or a fluorine atom are preferred.

The enantiomerically pure compounds of formula (I) in the form of saltswith L-(−)- or D-(+)-di-para-toluoyltartaric acid are preferred.

The compounds of formula (II), in the enantiomerically pure form, in theracemic form or in the form of a mixture of diastereoisomers, and theiroptional salts with inorganic or organic acids are novel and form partof the invention.

The compounds of formula (II) in which X represents a chlorine atom or afluorine atom are preferred.

The compounds of formula (II) in which R₁ represents a benzyl group or abenzyloxycarbonyl group are preferred.

According to another of its aspects, a subject matter of the inventionis a process B for the preparation of a compound, in theenantiomerically pure form or in the racemic form, of formula:

in which X represents a halogen atom and R₁ represents abenzyloxycarbonyl group or a 1-chloroethyloxycarbonyl group,characterized in that a compound, in the enantiomerically pure form orin the racemic form, of formula:

in which X is as defined for a compound of formula (II), is reacted withbenzyl chloroformate or 1-chloroethyl chloroformate in the presence of abase, with or without solvent.

Preferably, in process B, R₁ represents a benzyloxycarbonyl group.

The benzyl chloroformate or the 1-chloroethyl chloroformate is used inthe reaction in a proportion of 1 to 1.5 molar equivalents per molarequivalent of compound of formula (IIa).

The base used in the reaction is chosen from organic bases, such astriethylamine, N,N-diisopropylethylamine or N-methylmorpholine, or fromalkali metal carbonates or bicarbonates, such as sodium carbonate,potassium carbonate or sodium bicarbonate.

The base is used in the reaction in a proportion of 0.01 to 1.5 molarequivalents per molar equivalent of compound of formula (IIa).

When the reaction is carried out in a solvent, the latter is chosen froman aromatic hydrocarbon, such as toluene or xylene, a halogenatedhydrocarbon, such as dichloromethane, 1,2-dichloroethane, carbontetrachloride, chlorobenzene or dichlorobenzene, an ether, such astetrahydrofuran, dioxane or dimethoxyethane, an ester, such as ethylacetate, an amide, such as N,N-dimethylformamide, a nitrile, such asacetonitrile, or a ketone, such as acetone.

The reaction is carried out at a temperature of between −20° C. and thereflux temperature of the solvent and for a time of between 1 to 24hours.

According to another of its aspects, a subject matter of the inventionis a process C for the preparation of a compound, in theenantiomerically pure form, in the form of a mixture of diastereoisomersor in the racemic form, of formula:

in which X represents a halogen atom and R₁ represents a benzyl group, atert-butyloxycarbonyl group or an α-methylbenzyl group, of its optionalsalts with inorganic or organic acids, characterized in that a compound,in the enantiomerically pure form, in the form of a mixture ofdiastereoisomers or in the racemic form, of formula:

in which X and R₁ are as defined for a compound of formula (II), iscyclized and, optionally, the compound of formula (II) thus obtained isconverted to one of its salts.

Preferably, in process C, R₁ represents a benzyl group.

The reaction for the cyclization of a diol of formula (IV) to amorpholine derivative of formula (II) can be carried out according toknown methods as described, for example, in J. Med. Chem., 1994, 37,2791-2796.

Preferably, the cyclization reaction is carried out under phase transfercatalysis conditions using an alkylsulfonyl or arylsulfonyl halide inthe presence of a strong base and of a phase transfer catalyst, in aninert solvent as a mixture with water.

The reaction of the primary alcohol of the compound of formula (IV) withan alkylsulfonyl or arylsulfonyl halide in the presence of a strong basemakes it possible first to form an alkylsulfonate or arylsulfonate esterwhich, under the reaction conditions, cyclizes in situ to form themorpholine ring.

It has been found that, when the cyclization reaction of anenantiomerically pure compound of formula (IV) is carried out under theabovementioned conditions, an enantiomerically pure compound of formula(II) is obtained, the asymmetric carbon of which has the sameconfiguration.

Preference is given, among alkylsulfonyl or arylsulfonyl halides, tomethanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonylchloride.

The alkylsulfonyl or arylsulfonyl halide participates in the reaction ina proportion of 1 to 1.5 molar equivalents per molar equivalent ofcompound of formula (IV).

The base used during the reaction is chosen from an alkali metalhydroxide, such as sodium hydroxide or potassium hydroxide.

The base participates in the reaction in a proportion of 5 to 10 molarequivalents per molar equivalent of compound of formula (IV).

The phase transfer catalyst is chosen from substituted quaternaryammonium salts, such as benzyltriethylammonium chloride.

The catalyst participates in the reaction in a proportion of 0.01 to 0.1molar equivalent per molar equivalent of compound of formula (IV).

The reaction is carried out in an inert solvent, such as an aromatichydrocarbon, for example toluene or xylene.

The reaction is carried out at a temperature of between ambienttemperature and 60° C. and takes place over a period of 1 to 24 hours.

The compound of formula (IV), in the enantiomerically pure form, in theform of a mixture of diastereoisomers or in the racemic form, and itsoptional salts with inorganic or organic acids are novel and form partof the invention.

The compound of formula (IV) in which X represents a chlorine atom or afluorine atom is preferred.

The compound of formula (IV) in which R₁ represents a benzyl group ispreferred.

According to another of its aspects, a subject matter of the inventionis a process D for the preparation of a compound, in theenantiomerically pure form, of formula:

in which X represents a halogen atom and R₁ represents a benzyl group oran α-methylbenzyl group, of its salts with inorganic or organic acids,characterized in that:

a) a compound, in the racemic form, of formula:

in which X is as defined for a compound of formula (IV) and Halrepresents a halogen atom, is reacted with benzylamine or with R-(+)- orS-(−)-α-methylbenzylamine in the presence of a base in an inert solvent,to produce a compound, in the racemic form or in the form of a mixtureof diastereomers, of formula:

b) the enantiomers or the diastereoisomers of the compound of formula(VI) thus obtained are separated;

c) the enantiomerically pure compound of formula (VI) is reacted:

either with ethylene oxide in the catalytic presence of an acid in aninert solvent;

or with a compound of formula Hal″″-CH₂—CH₂—O—R₂ (XXI), in which R₂represents an O-protecting group and Hal″″ represents a halogen atom, inthe presence of a base in an inert solvent, followed by the deprotectionof the O-protecting group;

and, optionally, the enantiomerically pure compound of formula (IV) isconverted to one of its salts with inorganic or organic acids.

Preferably, in process D, R₁ represents a benzyl group.

Preferably, in stage a) of process D, use is made of a compound offormula (V) in which Hal represents a chlorine or bromine atom.

In stage a) of process D, the compound of formula (V) is first convertedto an intermediate epoxide derivative of formula:

which, under the reaction conditions, reacts with the amine to give thecompound of formula (VI).

The amine participates in the reaction in a proportion of 1 to 1.5 molarequivalents per molar equivalent of compound of formula (V).

The base used in the reaction is chosen from alkali metal carbonates orbicarbonates, such as sodium carbonate, potassium carbonate or sodiumbicarbonate. Preferably, sodium bicarbonate is used.

The base participates in the reaction in a proportion of 1 to 2 molarequivalents per molar equivalent of compound of formula (V).

The inert solvent is chosen from polar solvents, such as acetonitrile,propionitrile or 1-methyl-2-pyrrolidinone. Propionitrile constitutes apreferred solvent.

The reaction is carried out at a temperature of between 80° C. and 120°C.

The reaction is carried out over a period of 5 to 24 hours.

In stage b) of process D, the enantiomers of the compound of formula(VIa) thus obtained are separated according to conventional methods.Preferably, the separation can be carried out by preparation of anoptically active salt by the action of an optically active organic acid,such as L-(+)- or D-(−)-mandelic acid, L-(−)- orD-(+)-di-para-toluoyltartaric acid, L-(+)- or D-(−)-tartaric acid orL-(−)- or D-(+)-dibenzoyltartaric acid, and then separation of theisomers, for example by crystallization. The desired enantiomer isreleased from its salt in basic medium.

Preferably, the separation of the enantiomers of the compound of formula(VIa) is carried out by formation of an optically active salt by theaction of L-(+)- or D-(−)-mandelic acid.

In stage b) of process D, the diastereoisomers of the compound offormula (VIb) thus obtained are separated according to conventionalmethods. Preferably, the separation can be carried out by preparation ofa salt with an inorganic or organic acid or with an optically activeorganic acid, such as those mentioned above, and then separation of thediastereoisomers, for example by crystallization. The desireddiastereoisomer can be released from its salt in basic medium.

In stage c) of process D, the reaction of the enantiomerically purecompound of formula (VI) with ethylene oxide is carried out in a reactorof hydrogenator type, since, at the temperatures used, ethylene oxide isin the gaseous form.

The ethylene oxide participates in the reaction in a proportion of 5 to15 molar equivalents per molar equivalent of compound of formula (VI).

The solvent can, for example, be an alcohol, such as methanol.

The acid used in a catalytic amount in the reaction is chosen fromconventional inorganic or organic acids, such as hydrochloric acid oracetic acid.

It has been found that the reaction between the compound of formula (VI)and ethylene oxide can be carried out without acid catalysis by using,as starting compound, the enantiomerically pure compound of formula (VI)in the form of a salt with an optically active acid, preferably withL-(+)- or D-(−)-mandelic acid.

The reaction is carried out at a temperature of between 0° C. and 60° C.and is carried out for a time of between 2 and 24 hours.

According to the other alternative of stage c) of process D, theprotecting group R₂ is chosen from conventional O-protecting group wellknown to a person skilled in the art, such as the tetrahydropyran-2-ylgroup.

Use is preferably made of a compound of formula (XXI) in which Hal″″represents a chlorine or bromine atom.

The compound of formula (XXI) participates in the reaction in aproportion of 1 to 2 molar equivalents per molar equivalent of thecompound of formula (VI).

The base used in the reaction is chosen from alkali metal carbonates orbicarbonates, such as sodium carbonate, potassium carbonate or sodiumbicarbonate.

The base participates in the reaction in a proportion of 1 to 2 molarequivalents per molar equivalent of the compound of formula (VI).

The inert solvent is chosen from polar solvents, such as acetonitrile,propionitrile or 1-methyl-2-pyrrolidone.

The reaction is carried out at a temperature of between 80° C. and 120°C. and is carried out over a period of 5 to 24 hours.

The deprotection of the O-protecting group R₂ is carried out accordingto methods known to a person skilled in the art. For example, when R₂represents a tetrahydropyran-2-yl group, the deprotection is carried outby acid hydrolysis using an acid, such as hydrochloric acid.

The reaction is carried out in an ethereal solvent, such as diethylether, or an alcohol, such as methanol, or in an aromatic solvent, suchas toluene, at a temperature of between 0° C. and the reflux temperatureof the solvent and for a time of between 1 and 24 hours.

The compound of formula (VI), in the racemic form, in the form of amixture of diastereoisomers or in the enantiomerically pure form, andits salts with inorganic or organic acids or its salts with opticallyactive acids are novel and form part of the invention.

The enantiomerically pure compound of formula (VIa) in the form of asalt with L-(+)- or D-(−)-mandelic acid is preferred.

The compound of formula (VI) in which X represents a chlorine orfluorine atom is preferred.

The compound of formula (VI) in which R₁ represents a benzyl group ispreferred.

The compound of formula (XXI) is prepared by protection of 2-haloethanolderivatives according to conventional methods, such as those describedin Protective Groups in Organic Chemistry, J. F. W. McOmie, published byPlenum Press, 1973 and in Protective Groups in Organic Synthesis, T. W.Greene and P. G. M. Wutts, published by John Wiley and Sons, 1991.

According to another of its aspects, a subject matter of the inventionis a process E for the preparation of a compound, in the racemic form orin the form of mixture of diastereoisomers, of formula:

in which X represents a halogen atom and R₁ represents the benzyl group,the tert-butyloxycarbonyl group or the α-methylbenzyl group, of itsoptional salts with inorganic or organic acids, characterized in that:

a) a compound, in the racemic form, of formula:

in which X is as defined for a compound of formula (IV) and Halrepresents a halogen atom, is reacted either with2-(benzylamino)-1-ethanol or with 2-amino-1-ethanol or with (R)- or(S)-2-(α-methylbenzylamino)-1-ethanol in the presence of a base and inan inert solvent, and, optionally, the compound of formula (IVa) or(IVe) thus obtained is converted to one of its salts with inorganic ororganic acids;

b) if appropriate, when the compound of formula (V) is employed with2-amino-1-ethanol in stage a), the compound thus obtained, of formula:

is treated with di-tert-butyl dicarbonate in the presence of a base andin an inert solvent to produce the compound of formula (IVd).

Preferably, in process E, R₁ represents a benzyl group.

Preferably, in stage a) of process E, use is made of a compound offormula (V) in which Hal represents a chlorine or bromine atom.

As in stage a) of process D, the compound of formula (V) is firstconverted to an intermediate epoxide derivative of formula (VII) which,under the reaction conditions, reacts in situ with the aminoethanolderivative to give the compound of formula (IVa), (IVe) or (IV′d).

The aminoethanol derivative participates in the reaction in a proportionof 1 to 1.5 molar equivalents per molar equivalent of compound offormula (V).

The base used in the reaction is chosen from alkali metal carbonates orbicarbonates, such as sodium carbonate, potassium carbonate or sodiumbicarbonate. Preferably, sodium bicarbonate is used.

The base participates in a proportion of 1 to 2 molar equivalents permolar equivalent of compounds of formula (V).

The inert solvent is chosen from polar solvents, such as acetonitrile,propionitrile or 1-methyl-2-pyrrolidinone. 1-Methyl-2-pyrrolidinoneconstitutes a preferred solvent.

The reaction is carried out at a temperature of between 80 and 120° C.and for a time of between 10 and 24 hours.

If appropriate, in stage b) of process E, the compound of formula (IV′d)is reacted with di-tert-butyl dicarbonate in the presence of an organicbase, such as triethylamine, N,N-diisopropylethylamine orN-methylmorpholine, in an inert solvent, such as dichloromethane,tetrahydrofuran or N,N-dimethylformamide, and at a temperature ofbetween 0° C. and 60° C.

(R)- or (S)-2-(α-Methylbenzylamino)-1-ethanol is prepared according tothe method described in J. Am. Chem. Soc., 1984, 106, 747-754.

The compounds of formula (V) are novel and form part of the invention.

The compound of formula (V) in which X represents a chlorine atom or afluorine atom and Hal represents a chlorine or bromine atom ispreferred.

According to another of its aspects, a subject matter of the inventionis a process F for the preparation of a compound of formula:

in which X represents a halogen atom and Hal represents a halogen atom,characterized in that:

a) a compound of formula:

in which X is as defined for a compound of formula (V), is reacted witha compound of formula:Hal′-CO—CH₂-Hal  (IX)in which Hal′ and Hal represent a halogen atom, in the presence of aLewis acid and in an inert solvent, to produce a compound of formula:

b) the compound of formula (X) thus obtained is reacted with a compoundof formula:CH₂═CH—Mg-Hal″  (XI)in which Hal″ represents a halogen atom, in an inert solvent, followedby hydrolysis, and the expected compound of formula (V) is obtained.

According to a preferred aspect, the invention relates to thepreparation of a compound of formula (V) in which Hal represents achlorine or bromine atom.

Preferably, in stage a), use is made of a compound of formula (IX) inwhich Hal′ and Hal each independently represent a chlorine or bromineatom and, in stage b), use is made of a compound of formula (XI) inwhich Hal″ represents a chlorine or bromine atom.

Stage a) of process F is a Friedel-Crafts reaction carried out underPerrier conditions according to conventional methods.

The Lewis acid is chosen from conventional Lewis acids; preferablyaluminum chloride is used.

The Lewis acid is used in the reaction in a proportion of 1 to 1.5 molarequivalents per molar equivalent of compound of formula (VIII).

Preference is given, among haloacetyl halides of formula (IX), to theuse of chloroacetyl chloride.

The compound of formula (IX) is used in a proportion of 1 to 1.5 molarequivalents per molar equivalent of compound of formula (VIII).

The solvent is chosen from aromatic hydrocarbons, such as toluene orxylene, chlorinated hydrocarbons, such as dichloromethane,dichloroethane, carbon tetrachloride, chlorobenzene or dichlorobenzene,or ethers, such as tetrahydrofuran, dioxane or dimethoxyethane.Preferably, dichloromethane is used.

The reaction is carried out at a temperature of between 0° C. and 100°C. and for a time of between 1 and 24 hours.

Stage b) of process F is a Grignard reaction carried out according toconventional methods.

The compound of formula (XI) is used in the reaction in a proportion of1 to 1.5 molar equivalents per molar equivalent of compound of formula(X).

The solvent is chosen from ethers, such as diethyl ether, diisopropylether, tetrahydrofuran or dioxane. Preferably, tetrahydrofuran is used.

The reaction is carried out at a temperature of between −20° C. and 0°C. and for a time of between 1 and 24 hours.

At the end of the reaction, the reaction mixture is hydrolyzed accordingto conventional methods by pouring it, for example, onto a saturatedammonium chloride solution.

According to another of its aspects, a subject matter of the inventionis a process G for the preparation of a compound, in the racemic form,of formula:

in which X represents a halogen atom, of its salts with inorganic ororganic acids, characterized in that:

a) the preparation is carried out as in stage a) of process F;

b) the compound of formula (X) thus obtained is reacted with a compoundof formula:

in which R₂ represents an O-protecting group, in the presence of a baseand in an inert solvent, to produce a compound of formula:

c) the compound of formula (XIII) thus obtained is reacted with acompound of formula:CH₂═CH—Mg-Hal″  (XI)in which Hal″ represents a halogen atom, in an inert solvent, followedby hydrolysis, to produce a compound of formula:

d) the compound of formula (XIV) is deprotected and, optionally, thecompound of formula (IVa) thus obtained is converted to one of its saltswith inorganic or organic acids.

Preferably, in stage a), use is made of a compound of formula (IX) inwhich Hal′ and Hal each independently represent a chlorine or bromineatom.

In stage b) of process G, the protecting group R₂ is chosen fromconventional O-protecting groups well known to a person skilled in theart, such as the tetrahydropyran-2-yl group.

The compound of formula (XII) participates in the reaction in aproportion of 1 to 1.5 molar equivalents per molar equivalent ofcompound of formula (X).

The base is chosen from alkali metal carbonates or bicarbonates,preferably sodium bicarbonate.

The base is used in a proportion of 1 to 1.5 molar equivalents per molarequivalent of compound of formula (X).

The inert solvent is chosen from polar solvents, such as acetonitrile orpropionitrile, or ethers, such as tetrahydrofuran, or halogenatedsolvents, such as dichloromethane. Preferably, tetrahydrofuran is used.

The reaction is carried out at a temperature of between ambienttemperature and the reflux temperature of the solvent and for a time ofbetween 1 and 24 hours.

Stage c) of process G is a Grignard reaction carried out according toconventional methods.

Preferably, in stage c), use is made of a compound of formula (XI) inwhich Hal″ represents a chlorine or bromine atom.

The compound of formula (XI) is used in the reaction in a proportion of1.5 to 2 molar equivalents per molar equivalent of compound of formula(XIII).

The solvent is chosen from ethers, such as diethyl ether, diisopropylether, tetrahydrofuran or dioxane. Preferably, use is made oftetrahydrofuran.

The reaction is carried out at a temperature of between ambienttemperature and the reflux temperature of the solvent and takes placefor a time of between 1 and 24 hours.

At the end of the reaction, the reaction mixture is hydrolyzed bypouring it, for example, onto a saturated ammonium chloride solution.

The compound of formula (XIV) is deprotected in stage d) of process Gaccording to methods known to a person skilled in the art. For example,when R₂ represents a tetrahydropyran-2-yl group, deprotection is carriedout by acid hydrolysis using an acid, such as hydrochloric acid. Thelatter can be generated in situ from acetyl chloride and methanol.

The reaction is carried out in an ethereal solvent, such as diethylether, or an alcohol, such as methanol, at a temperature of between 0°C. and the reflux temperature of the solvent and for a time of between 1and 24 hours.

The compound of formula (XIII) and its salts with inorganic or organicacids are novel and form part of the invention.

The compound of formula (XIII) in which X represents a chlorine orfluorine atom is preferred.

The compound of formula (XIV) and its salts with inorganic or organicacids are novel and form part of the invention.

The compound of formula (XIV) in which X represents a chlorine orfluorine atom is preferred.

The compound of formula (XII) is prepared by protection of the2-(benzylamino)-1-ethanol according to conventional methods, such asthose described in Protective Groups in Organic Chemistry, J. F. W.McOmie, published by Plenum Press, 1973 and in Protective Groups inOrganic Synthesis, T. W. Greene and P. G. M. Wutts, published by JohnWiley and Sons, 1991.

According to another of its aspects, a subject matter of the inventionis an enantioselective process H for the preparation of a compound, inthe enantiomerically pure form, of formula:

in which X represents a halogen atom, of its salts with inorganic ororganic acids, characterized in that:

a) a compound of formula:

in which X is as defined for a compound of formula (IVa) and Hal′″represents a halogen atom, is reacted with methyl (R)- or(S)-2-phenylhexahydropyrrolo-[1,2-c]imidazole-3-carboxylate, of formula:

in the presence of magnesium chloride in an inert solvent, followed byhydrolysis, to produce a compound, in the enantiomerically pure form, offormula:

b) the compound of formula (XVII) thus obtained is reacted with acompound of formula:CH₂═CH—Mg-Hal″  (XI)in which Hal″ represents a halogen atom, in an inert solvent, followedby hydrolysis, to produce a compound, in the enantiomerically pure form,of formula:

c) the compound of formula (XVIII) thus obtained is hydrolyzed by theaction of an acid in an inert solvent as a mixture with water, toproduce a compound, in the enantiomerically pure form, of formula:

d) the compound of formula (XIX) thus obtained is reacted with2-(benzylamino)-1-ethanol in the presence of an acid in an inertsolvent, then the iminium salt formed as an intermediate is reduced bymeans of a reducing agent and, optionally, the enantiomerically purecompound of formula (IVa) is converted to one of its salts withinorganic or organic acids.

Preferably, in stage a), use is made of a compound of formula (XV) inwhich Hal′″ represents a chlorine or bromine atom and, in stage b), useis made of a compound of formula (XI) in which Hal″ represents achlorine or bromine atom.

Stages a), b) and c) of process H are carried out according to themethod for asymmetric synthesis of α-hydroxyaldehydes described by T.Mukaiyama in Tetrahedron, 1981, 37 (23), 4111-4119.

In stage d), an α-hydroxyaldehyde of formula (XIX) is reacted with2-(benzylamino)-1-ethanol in the presence of an acid, such as aceticacid, in a polar solvent, such as acetonitrile, to form in situ anintermediate imine which is reduced chemically using, for example,sodium triacetoxyborohydride or sodium cyanoborohydride or catalyticallyusing hydrogen and a catalyst, such as palladium-on-charcoal.

The enantiomerically pure or racemic compound of formula (XIX) is noveland forms part of the invention.

The compound of formula (XIX) in which X represents a chlorine orfluorine atom is preferred.

According to another of its aspects, a subject matter of the inventionis an enantioselective process I for the preparation of a compound, inthe enantiomerically pure form, of formula:

in which X represents a halogen atom, of its salts with inorganic ororganic acids, characterized in that:

a) b) c) the preparation is carried out as in stages a), b) and c) ofprocess H;

d) the compound of formula (XIX) thus obtained is reduced by means of areducing agent in an inert solvent to produce an enantiomerically purecompound of formula:

e) the compound of formula (XX) thus obtained is cyclized to produce acompound, in the enantiomerically pure form, of formula:

f) the compound of formula (VII) thus obtained is reacted with2-(benzylamino)-1-ethanol in the presence of a base and in an inertsolvent and, optionally, the enantiomerically pure compound of formula(IVa) is converted to one of its salts with inorganic or organic acids.

In stage d), the reduction of the aldehyde of formula (XIX) to a diol offormula (XX) is carried out according to conventional methods using areducing agent, such as sodium borohydride, diisobutylaluminum hydrideor lithium aluminum hydride. Preferably, sodium borohydride is used.

The reaction is carried out in an inert solvent, such as an aromaticsolvent, for example toluene, an alcohol, for example ethanol, an ether,for example tetrahydrofuran, or a mixture of these solvents.

The reaction is carried out at a temperature of between −70° C. and thereflux temperature of the solvent and for a time of between 1 and 24hours.

In stage e), the cyclization of a diol of formula (XX) to an oxiranederivative of formula (VII) is carried out, preferably, under phasetransfer catalysis conditions using an alkylsulfonyl or arylsulfonylhalide in the presence of a strong base and of a phase transfercatalyst, in an inert solvent as a mixture with water.

It has been found that, when the cyclization reaction of anenantiomerically pure compound of formula (XX) is carried out under theabovementioned conditions, an enantiomerically pure compound of formula(VII) is obtained, the asymmetric carbon atom of which has the sameconfiguration.

Preference is given, among alkylsulfonyl or arylsulfonyl halides, tomethanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonylchloride.

The alkylsulfonyl or arylsulfonyl halide participates in the reaction ina proportion of 1 to 1.5 molar equivalents per molar equivalent ofcompound of formula (XX).

The base used during the reaction is chosen from an alkali metalhydroxide, such as sodium hydroxide or potassium hydroxide.

The base participates in the reaction in a proportion of 5 to 10 molarequivalents per molar equivalent of compound of formula (XX).

The phase transfer catalyst is chosen from substituted quaternaryammonium salts, such as benzyltriethylammonium chloride.

The catalyst participates in the reaction [lacuna] of 0.01 to 0.1 molarequivalent per molar equivalent of compound of formula (XX).

The reaction is carried out in an inert solvent, such as an aromatichydrocarbon, for example toluene or xylene, or a chlorinated solvent,for example dichloromethane.

The reaction is carried out at a temperature of between ambienttemperature and 60° C. and for a time of between 1 and 24 hours.

In stage f), the opening of the oxirane derivative of formula (VII) by2-(benzylamino)-1-ethanol is carried out according to conventionalmethods.

The amine participates in the reaction in a proportion of 1 to 1.5 molarequivalents per molar equivalent of compound of formula (VII).

The base is chosen from alkali metal carbonates or bicarbonates, such assodium carbonate, potassium carbonate or sodium bicarbonate.

The base participates in the reaction in a proportion of 1 to 2 molarequivalents per molar equivalent of compound of formula (VII).

The solvent is chosen from polar solvents, such as acetonitrile,propionitrile or 1-methyl-2-pyrrolidinone.

The reaction is carried out at a temperature of between ambienttemperature and 120° C. and for a time of between 1 to 48 hours.

It has been found that, when the reaction for opening theenantiomerically pure compound of formula (VII) is carried out under theabovementioned conditions, a compound of formula (IVa) is obtained inwhich the asymmetric carbon atom has the same configuration.

The enantiomerically pure or racemic compound of formula (XX) is noveland forms part of the invention.

The compound of formula (XX) in which X represents a chlorine orfluorine atom is preferred.

The enantiomerically pure or racemic compound of formula (VII) is noveland forms part of the invention.

The compound of formula (VII) in which X represents a chlorine orfluorine atom is preferred.

The compound of formula (XVI) used in stage a) of process H or in stagea) of process I is prepared from (S)- or (R)-proline according to theprocesses described in Tetrahedron, 1981, 37 (23), 4111-4119, and asillustrated in the examples.

During each of the above processes A to I or during the variousconstituent stages of these processes, the compounds of formula (I),(IIa), (IIb), (IIc), (IId), (IIe), (III), (IVa), (IVd), (IVe), (IV′d),(V), (VIa), (VIe), (VIII), (X), (XIII), (XIV), (XVII), (XVIII), (XIX)and (XX) thus obtained can subsequently be separated from the reactionmedium according to conventional methods, such as extraction,crystallization, distillation or chromatography. Furthermore, thevarious abovementioned compounds obtained can either be isolated or canbe charged directly to the following process or the following stage inthe medium in which they have been obtained. Each of the processes A toI or each of the constituent stages of these processes can thus becombined for the preparation of the compounds of formula (I).

If appropriate, the compounds of formula (I), (IIa), (IIe), (IIIa),(IIIe), (IVa), (IVe), (IV′d), (VIa), (VIe), (XIII) and (XIV) thusobtained can be isolated in the free base or salt form according toconventional techniques.

These salts comprise those with inorganic or organic acids which makepossible suitable separation or crystallization of the compounds offormula (I), (IIa), (IIe), (IIIa), (IIIe), (IVa), (IVe), (IV′d), (VIa),(VIe), (XIII) and (XIV), such as the hydrochloride, hydrobromide,sulfate, hydrogensulfate, dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate, succinate, naphthalene-2-sulfonate,glyconate, gluconate, citrate, isethionate, benzenesulfonate orpara-toluenesulfonate.

When the compounds of formula (I), (IIa), (IIe), (IIIa), (IIIe), (IVa),(IVe), (IV′d), (VIa), (VIe), (XIII) and (XIV) are obtained in the freebase form, salification is carried out by treatment with the chosen acidin an organic solvent. The corresponding salt is obtained by treatmentof the free base, dissolved, for example, in an ether, such as diethylether, or in an alcohol, such as methanol, ethanol or propan-2-ol, or inacetone or in dichloromethane or in ethyl acetate, with a solution ofthe chosen acid in one of the abovementioned solvents, which salt isisolated according to conventional techniques.

Thus, for example, the hydrochloride, hydrobromide, sulfate,hydrogensulfate, dihydrogenphosphate, methanesulfonate,benzenesulfonate, para-toluenesulfonate, oxalate, maleate, succinate,fumarate or naphthalene-2-sulfonate is prepared.

The compounds of formula (I), (IIa), (IIe), (IIIa), (IIIe), (IVa),(IVe), (IV′d), (VIa), (VIe), (XIII) and (XIV) can be isolated in theform of one of their salts, for example the hydrochloride or oxalate; inthis case, if necessary, the free base can be prepared by neutralizationof said salt with an inorganic or organic base, such as sodium hydroxideor triethylamine, or with an alkali metal carbonate or bicarbonate, suchas sodium carbonate, sodium bicarbonate, potassium carbonate orpotassium bicarbonate.

According to a preferred aspect, a subject matter of the invention isprocesses A to I for the preparation of compound of formula (I), (IIa),(IIb), (IIc), (IId), (IIe), (IVa), (IVd), (IVe) and (V) in which Xrepresents a chlorine atom or a fluorine atom.

According to another preferred aspect, a subject matter of the inventionis compounds of formula (I), in the form of optically active salts withoptically active organic acids, (II), (IV), (V), (VI), (VII), (XIII),(XIX) and (XX) in which X represents a chlorine atom or a fluorine atom.

Thus, according to the invention, the compounds of formula (I) areprepared by using the above processes A to I and by following thesynthetic routes defined below and as illustrated in the examples:

synthetic route I: process F, stages a and b; then process E, stage a orstage a and b; then process C; then process A, stages a, b and c.

synthetic route II: process F, stages a and b; then process D, stages a,b and c; then process C; then process A, stages a, b.

synthetic route III: process G, stages a, b, c and d; then process C;then process A, stages a, b and c.

synthetic route IV: process H, stages a, b, c and d; then process C;then process A, stages a and b.

synthetic route V: process I, stages a, b, c, d, e and f; then processC; then process A, stages a and b.

synthetic routes VI to X: identical to synthetic routes I to Vrespectively but carrying out process B between process C and process A.

The following examples illustrate the invention without, however,limiting it.

In the examples below, the following abbreviations are used:

-   DCM: dichloromethane-   THF: tetrahydrofuran-   AT: ambient temperature.

The proton nuclear magnetic resonance (¹H NMR) spectra are recorded at200 MHz in d₆-DMSO using the d₆-DMSO peak as reference. The chemicalshifts δ are expressed in parts per million (ppm). The signals observedare expressed thus: s: singlet; d: doublet; d.d: double doublet; t:triplet; d.t.: double triplet; q: quartet; m: multiplet.

The enantiomeric purities were determined by analysis by HighPerformance Liquid Chromatography (HPLC) on a Chiracel OD or AD chiralphase (cellulose-based stationary phases) and by supercritical HPLC.

EXAMPLE 1 Synthetic Route I

(R)-(+)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, salt withL-(−)-di-para-toluoyltartaric acid.

(I): X═F

A) 2-Chloro-1-(3,4-difluorophenyl)ethanone.

(X): X═F; Hal=Cl; process F, stage a).

227.6 g of chloroacetyl chloride (IX: Hal=Hal′=Cl) are added over 10minutes under a nitrogen atmosphere to a suspension of 247.7 g ofaluminum chloride in 450 ml of DCM and then the yellow solution obtainedis heated to reflux. 200 g of 1,2-difluorobenzene (VIII: X═F) aresubsequently added dropwise over 2 hours and then the reaction mixtureis maintained at reflux for 1 hour. After cooling the red-coloredreaction mixture to 20° C., the latter is run onto 1 kg of ice and leftstirring for 30 minutes. After separating by settling, the organic phaseis removed, the aqueous phase is extracted with 500 ml of DCM, thecombined organic phases are washed with 2×500 ml of water, with 500 mlof a saturated NaHCO₃ solution and with 500 ml of water, the organicphase is dried over MgSO₄ and the solvent is evaporated under vacuum.327.6 g of the expected product are obtained in the form of alachrymatory yellow oil.

Yield: 97.6% ¹H NMR: δ (ppm): 5.2: s: 2H; 7.6: dd: 1H; 7.8: m: 1H; 8.0:dd: 1H.

B) 1-Chloro-2-(3,4-difluorophenyl)but-3-en-2-ol.

(V) X═F; Hal=Cl; process F, stage b).

800 ml of a 1M solution of vinylmagnesium bromide (XI: Hal″=Br) in THFare cooled to −10° C. under a nitrogen atmosphere, a solution of 152.4 gof the compound obtained in the preceding stage in 800 ml of THF isadded over 4 hours 30 minutes while maintaining the bulk temperature at−10° C., and then the reaction mixture is left stirring for 20 minutesat a temperature of −10° C. The reaction mixture is hydrolyzed byrunning it onto 2 liters of a saturated aqueous ammonium chloridesolution and is left stirring for 30 minutes. After separating bysettling, the organic phase is washed with 2×1 liter of a saturated NaClsolution and then the organic phase is filtered to remove the inorganicsalts. 1.5 liters of a solution of the expected compound in THF areobtained, which solution is used directly in the following stage.

¹H NMR: δ (ppm): 3.9: dd: 2H; 5.3: dd: 2H; 5.9: s: 1H; 6.2: m: 1H;7.3-7.5: m: 3H.C) 1-[Benzyl(2-hydroxyethyl)amino]-2-(3,4-difluoro-phenyl)but-3-en-2-ol.

A mixture of 67.2 g of NaHCO₃ and 133 g of 2-(benzylamino)-1-ethanol in500 ml of 1-methyl-2-pyrrolidinone is heated to 120° C. and then thesolution of the compound obtained in the preceding stage in THF (1.5liters) is run in over 3 hours while distilling off the THF from itsintroduction into the reaction medium. After distilling off 1.5 litersof THF, the reaction mixture is left stirring for 12 hours at 120° C.After cooling to 20° C., the reaction mixture is run onto 2 liters ofwater, the mixture is extracted with 2 liters of toluene and then theorganic phase is washed with 2×500 ml of water. 2 liters of water areadded to the organic phase, and 75 ml of a concentrated HCl solution arerun in. The acidic aqueous phase is washed with 500 ml of toluene, theaqueous phase is basified by addition of 96 ml of a 10N NaOH solutionand extracted with 1.2 liters of toluene, and the organic phase iswashed with 500 ml of water. 1.23 kg of toluene solution comprising theexpected compound are obtained, which solution is used directly in thefollowing stage.

A dry residue from 50 g of solution comprises 8.9 g of the expectedcompound, i.e., with respect to the entire solution, 219 g of theexpected compound.

Yield: 82%, calculated from the starting compound of stage B of formula(X): X═F; Hal=Cl. ¹H NMR: δ (ppm): 2.5: q: 2H; 2.9: s: 2H; 3.3: q: 2H;3.6: dd: 2H; 4.5: t: 1H; 5.2: dd: 2H; 5.5: s: 1H; 6.3: dd: 1H; 7.1-7.5:m: 8H.D) 4-Benzyl-2-(3,4-difluorophenyl)-2-vinylmorpholine maleate.

The toluene solution of the compound obtained in the preceding stage isstirred at 760 rev/min, 7.5 g of benzyltriethylammonium chloride areadded and then a freshly prepared and hot solution of 215.5 g of NaOHpellets in 215 ml of water is added, the temperature of the reactionmedium rising to 48° C. 139.23 g of benzenesulfonyl chloride are thenadded dropwise over 2 hours at a flow rate which makes it possible tomaintain the bulk temperature at 45° C. After cooling the reactionmixture to 20° C., it is hydrolyzed by addition of 1 liter of water andleft stirring for 1 hour. After separating by settling, the organicphase is washed with 2×1 liter of water (pH=7) and dried over MgSO₄, andthe solvent is evaporated under vacuum. 200 g of the expected compoundare obtained in the free base form.

Yield: 96.5%.

A suspension of 94.7 g of maleic acid in 530 ml of AcOEt is heated atreflux for 10 minutes and then a solution of 257.3 g of the free basecompound (IIa: X═F) in 116 ml of AcOEt is added. The reaction mixture isallowed to return to ambient temperature and, at 43° C., crystallizationis initiated by addition of 1 g of maleate of the compound (IIa: X═F) toproduce rapid precipitation. The reaction mixture is cooled to 0° C. andleft stirring for 12 hours. The crystallized product is filtered off,washed with 3×100 ml of cold AcOEt and dried under vacuum at 30° C. 250g of the expected compound are obtained in the maleate form.

Yield of the salification: 71%. ¹H NMR: δ (ppm): 2.5: m: 2H; 2.9: dd:2H; 3.7: m: 2H+2H; 5.7: dt: 2H; 5.9: dd: 1H; 6.1: s: 2H; 7.1-7.6: m: 8H.E) 2-[4-Benzyl-2-(3,4-difluorophenyl)morpholin-2-yl]-1-ethanolhydrochloride.

1 liter of a 0.5M solution of 9-bora-bicyclo[3.3.1]nonane in THF isintroduced into a “pilot system” reactor (temperature of the oil in thejacket automatically controlled by the bulk temperature) placed under anitrogen atmosphere and 500 ml of THF are distilled off at atmosphericpressure with a bulk temperature of 74° C. An exchange of solvent atconstant volume is then carried out by introduction of 500 ml oftoluene, the exchange lasting 3 hours and the final temperature being110° C. The mass is cooled to a temperature of 20° C. and theprecipitation of the dimer of 9-borabicyclo[3.3.1]nonane is observed. Asolution of 131.4 g of the compound obtained in the preceding stage, inthe free base form, in 150 ml of toluene is subsequently added over 25minutes and the reaction mixture is left stirring for 12 hours. Thereaction mixture is cooled to 5° C. and stirred at 500 rev/min, and 50ml of a 10N NaOH solution and then 7 g of tetrabutylammoniumhydrogensulfate are added. The bulk temperature preset value is adjustedto 20° C. and 60 g (53 ml) of an 11M solution of hydrogen peroxide inwater (33%, 130 volumes, d=1.13) are added at a flow rate by mass of 1g/min. The bulk preset value is then adjusted to 35° C. and 60 g of the11M hydrogen peroxide solution are added at a flow rate by mass of 1.5g/min. Finally, the bulk preset value is adjusted to 50° C. and 60 g ofthe 11M hydrogen peroxide solution are added at a flow rate by mass of 3g/min. The mixture is left stirring for 1 hour at a temperature of 50°C. After separating by settling under warm conditions, three phases areobserved: toluene/cis-1,5-cyclooctanediol/-water. After removing theaqueous phase, the mixture is cooled to 20° C. and the toluene phase iswashed with 3×200 ml of water to remove the diol. The residual water isremoved from the toluene phase by azeotropic entrainment at constantvolume with 200 ml of toluene. 1 g of hydrochloride of the expectedcompound (IIIa: X═F) is then added to the clear toluene phase thusobtained and then 68 ml of a 6.1M solution of HCl in ethanol are addeddropwise over 40 minutes. The mixture is cooled to 20° C. and leftstirring for 3 hours, and the precipitate formed is filtered off, washedwith 3×100 ml of toluene and dried under vacuum at 30° C. 124.3 g of theexpected compound are obtained in the hydrochloride form.

Yield: 80.6%. ¹H NMR: δ (ppm): 2.0: m: 2H; 3.0: m: 2H; 3.2: m: 2H; 3.4:m: 2H; 4.0: dd: 2H; 4.4: s: 2H; 7.1-7.8: m: 8H.

F) 2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, racemic.

(I): X═F, process A, stage b).

26 g of 50% wet 10% palladium-on-charcoal are introduced into ahydrogenation reactor purged with nitrogen, then a solution of 236.3 gof the compound obtained in the preceding stage in the free base form in2.6 liters of MeOH is run in and 53 ml of a concentrated HCl solutionare added. Hydrogenation is carried out under a pressure of 3 bar at atemperature of 40° C. for 1 hour. The reaction mixture is cooled to 20°C. and filtered through a Whatman® filter paper, the filter paper iswashed with 500 ml of MeOH and the filtrate is concentrated under vacuumto a volume of 500 ml. An exchange of solvent with 500 ml of water iscarried out, 80 ml of 10N NaOH are then added to the aqueous solutionthus obtained and the mixture is left stirring for 1 hour at 15° C. Theprecipitate formed is filtered off, washed with 200 ml of water, takenup in 400 ml of diisopropyl ether and left stirring for 1 hour. Theprecipitate is filtered off, washed with 200 ml of diisopropyl ether anddried under vacuum overnight at 40° C. 120 g of the expected product areobtained.

Yield: 78%.

G) (R)-(+)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, salt withL-(−)-di-para-toluoyltartaric acid.

(I): X═F; process A, stage c).

A suspension of 60 g of the compound obtained in the preceding stage in780 ml of MeOH is heated to 40° C. It is stirred at 240 rev/min and asolution of 95.3 g of L-(−)-di-para-toluoyltartaric acid in 300 ml ofMeOH is added over 50 minutes while maintaining the bulk temperature at40° C. The reaction mixture is subsequently left stirring for 10 minutesat 40° C. and then for 1 hour at 35° C., and is cooled to 20° C. over 2hours 30 minutes. The mixture is left stirring for 12 hours at 20° C.and the precipitate formed is filtered off, taken up in 150 ml of MeOHand left stirring for 30 minutes. The precipitate is again filtered off,washed with 60 ml of MeOH and dried under vacuum at 40° C. 64.3 g of theexpected compound are obtained in the form of a salt withL-(−)-di-para-toluoyltartaric acid.

Yield: 41.3%. Final yield: 14.2%, calculated from the starting compoundof stage A of formula (VIII): X═F. Enantiomeric purity: 97.5%(e.e.=95%).

EXAMPLE 2 Synthetic Route II

(R)-(+)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol.

(I): X═F.

A) 2-Chloro-1-(3,4-difluorophenyl)ethanone.

(X): X═F; Hal=Cl; process F, stage a).

The procedure is identical to that of stage A of example 1.

B) 1-Chloro-2-(3,4-difluorophenyl)but-3-en-2-ol.

(V): X═F; Hal=Cl; process F, stage b).

560 ml of a 1.8M solution of vinylmagnesium chloride (XI: Hal″=Cl) inTHF are cooled to −15° C. under a nitrogen atmosphere and a solution of170 g of the compound obtained in the preceding stage in 510 ml of THFis added over 2 hours while maintaining the bulk temperature at −15° C.The reaction mixture is hydrolyzed by running it onto 1 liter ofsaturated aqueous ammonium chloride solution and is left stirring for 1hour at ambient temperature. After separating by settling, the organicphase is washed with 2×1 liter of a saturated aqueous NaCl solution. 840ml of a solution of the expected compound in THF are obtained, whichsolution is used directly in the following stage.C) 1-(Benzylamino)-2-(3,4-difluorophenyl)but-3-en-2-ol.

A mixture of 81 g of NaHCO₃ and 112.7 g of benzylamine in 190 ml of THFis heated to reflux and 300 ml of the solution of the compound obtainedin the preceding stage in THF are quickly added. As soon as reflux isagain reached, the THF is distilled off at constant volume while addingthe remainder of the preceding solution (540 ml). At the end of theaddition, the reaction mixture is concentrated to a THF volume of 400ml. An exchange of solvent is then carried out at constant volume with580 ml of propionitrile, the bulk temperature being 85° C. at the end ofthe exchange. The mixture is left stirring at 85° C. for 8 hours. Thepropionitrile is then removed by solvent exchange at constant volume byaddition, over 4 hours 30 minutes, of 1.1 liters of toluene, the bulktemperature being 106° C. at the end of the exchange. After cooling toambient temperature, 1.3 liters of toluene are added to produce 1.9liters of final solution and then the toluene phase is washed with 2liters of an aqueous solution comprising 12.5 ml of acetic acid. 1.3liters of an aqueous solution comprising 80 ml of concentrated HCl areadded to the organic phase and the volume is made up by addition of 400ml of toluene and of the sufficient amount of water to obtain 2.5 litersof aqueous phase, in order to dissolve the oil obtained. Afterextraction and separation by settling, the organic phase is washed with500 ml of water and the aqueous phases are combined. The aqueous phasesare basified by the addition of 105 ml of 10N NaOH and extracted with1.3 liters and then with 0.7 liter of diisopropyl ether, the combinedorganic phases are washed with 3×2 liters of water and dried over MgSO₄,and the solvent is evaporated under vacuum. 163 g of the expectedproduct are obtained.

Yield: 64%, calculated from the starting compound of stage B of formula(X): X═F; Hal=Cl. ¹H NMR: δ (ppm): 3.2: dd: 2H; 4.1: s: 2H; 5.2-5.4: dd:2H; 6.1-6.3: dd: 1H; 7.2-7.6: m: 8H.D) R-(+)-1-(Benzylamino)-2-(3,4-difluorophenyl)but-3-en-2-ol, salt withL-(+)-mandelic acid.

A suspension of 36.25 g of L-(+)-mandelic acid in 1.1 liters ofdiisopropyl ether is heated to 60° C., a solution of 137.9 g of thecompound obtained in the preceding stage in 555 ml of diisopropyl etheris added over 4 hours and then, at the end of the addition, the reactionmedium is heated at 75° C. for 1 hour 30 minutes to dissolve theprecipitate already formed. The reaction mixture is cooled to 20° C.using a cooling slope at the rate of 0.3° C./min and is left stirring at20° C. for 8 hours. The precipitate formed is filtered off, resuspendedin 600 ml of diisopropyl ether, again filtered off and dried undervacuum at 30° C. 103 g of the expected compound are obtained. Thecompound is taken up in 720 ml of AcOEt and heated to 60° C. using atemperature slope at the rate of 1° C./min, and the solution obtained iskept stirred at 60° C. for 15 minutes. It is cooled to 0° C. with acooling slope of 1° C./min, crystallization is initiated and the mixtureis left stirring at 0° C. for 4 hours. The precipitate formed isfiltered off, washed with 150 ml of diisopropyl ether and dried undervacuum at 30° C. 60 g of the expected compound are obtained in the formof the salt with L-(+)-mandelic acid.

Yield: 28.5%. Enantiomeric purity: 97.4% (e.e.: 94.8%). α_(D) ²⁵ =+44.6°(c=1, MeOH).E)(R)-(+)-1-[Benzyl(2-hydroxyethyl)amino]-2-(3,4-difluorophenyl)but-3-en-2-ol.

A solution of 70.25 g of the compound obtained in the preceding stage in200 ml of MeOH is introduced into a Parr reactor, the reactor is placedunder vacuum and the solution is cooled to 0° C. Ethylene oxide,preheated to 30° C., is subsequently introduced to a pressure of 1 barand then the reaction medium is slowly heated to 40° C. and leftstirring for 4 hours. After having vented off the ethylene oxide andthen purged the reaction medium by bubbling with nitrogen, the MeOH isconcentrated under vacuum. The residual oil is taken up in 250 ml ofwater, the aqueous phase is acidified by addition of 13 ml ofconcentrated HCl, the acidic aqueous phase is washed with 2×250 ml ofmethyl tert-butyl ether, and the aqueous phase is basified by additionof 18 ml of 10N NaOH and extracted with 2×250 ml of toluene. Thecombined organic phases are chromatographed on 500 g of silica, elutionbeing carried out with 5×250 ml of a toluene/AcOEt (50/50; v/v) mixture.The phases are combined and the solvents are concentrated under vacuum.43.5 g of the expected compound are obtained.

Yield: 81%. α_(D) ²⁵=+13.9° (c=1, MeOH).F) (R)-(+)-4-Benzyl-2-(3,4-difluorophenyl)-2-vinylmorpholinehydrochloride.

A solution of 40 g of the compound obtained in the preceding stage in200 ml of toluene is stirred at 760 rev/min, 1.4 g ofbenzyltriethylammonium chloride are added and then a freshly preparedand hot solution of 40 g of NaOH pellets in 40 ml of water is added, thetemperature of the reaction medium rising to 48° C. 25.43 g ofbenzenesulfonyl chloride are then added dropwise over 1 hour at a flowrate which makes it possible to maintain the bulk temperature at 45° C.After cooling the reaction mixture to 20° C., it is hydrolyzed byaddition of 200 ml of water and is left stirring for 1 hour. Afterseparating by settling, the organic phase is washed with 2×200 ml ofwater (pH=7) and dried over MgSO₄.20 ml of a 6.1M solution of HCl inethanol are added dropwise to the toluene solution thus obtained, themixture is left stirring for 1 hour and the solvents are concentratedunder vacuum. The residue is taken up in 200 ml of toluene and stirred,and the precipitate formed is filtered off. The precipitate is washedwith 100 ml of toluene and is dried under vacuum at 30° C. 37 g of theexpected compound are obtained in the hydrochloride form.

Yield: 87%. α_(D) ²⁵=+19.7° (c=1, MeOH).G) R-(+)-2-[4-Benzyl-2-(3,4-difluorophenyl)morpholin-2-yl]-1-ethanolhydrochloride.

100 ml of THF are distilled off under vacuum, under a nitrogenatmosphere, from 200 ml of a 0.5M solution of 9-borabicyclo[3.3.1]nonanein THF. A solvent exchange at constant volume is then carried out byintroduction of 100 ml of toluene and then the solution obtained iscooled to 20° C. (precipitation of the dimer of 9-BBN). A solution of 30g of the compound obtained in the preceding stage in the free base formin 35 ml of toluene is added and the mixture is left stirring for 8hours. 11 ml of a 10N NaOH solution are subsequently added, followed by1.6 g of tetrabutyl-ammonium hydrogensulfate dissolved in 2 ml of water.The reaction mixture is stirred at 500 rev/min and heated to a bulktemperature of 45° C., 31 g of an 11M solution of hydrogen peroxide inwater (33%, 130 volumes, d=1.13) are added over 40 minutes at a flowrate which makes it possible to maintain 45° C. in the reaction medium,and the reaction medium is left stirring at 45° C. for 15 minutes. Afterseparating by settling, the alkaline aqueous phase is removed, 100 ml ofwater are added to dissolve the cis-1,5-cyclooctanediol in the form ofan oil, and the mixture is stirred and cooled to 20° C. After separatingby settling, the organic phase is washed with 2×100 ml of water and theresidual water is removed from the organic phase by azeotropicentrainment at constant volume until a clear phase is obtained. 16.4 mlof a 6.1M solution of HCl in ethanol are then added dropwise and themixture is left stirring at 20° C. for 1 hour. The precipitate formed isfiltered off, washed with 3×20 ml of toluene and dried under vacuum at40° C. 28 g of the expected product are obtained in the hydrochlorideform.

Yield: 90%. α_(D) ²⁵=+41.6° (c=1, MeOH).

H) R-(+)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol.

(I): X═F; process A, stage b).

A solution of 30 g of the compound obtained in the preceding stage in300 ml of MeOH is added under a nitrogen atmosphere to 3 g of 50% wet10% palladium-on-charcoal, followed by 30 ml of toluene. Hydrogenationis carried out under a pressure of 1 bar at a temperature of 30° C. Thecatalyst is filtered off through a Whatman® filter paper, the filterpaper is washed with MeOH and then a solvent exchange is carried out onthe filtrate with 120 ml of water. After cooling, the aqueous phase iswashed with 2×120 ml of methyl tert-butyl ether, the aqueous phase isbasified by the addition of 9 ml of 10N NaOH and the aqueous phase isleft stirring for 1 hour under cold conditions. The precipitate formedis filtered off, washed with 100 ml of diisopropyl ether and dried undervacuum at 40° C. 14 g of the expected product are obtained.

Yield: 65%. Final yield: 7.3%, calculated from the starting compound ofstage A of formula (VIII): X═F. α_(D) ²⁵=+21.9° (c=1, MeOH).Enantiomeric purity: 99% (e.e.=98%).

EXAMPLE 3 Synthetic Route III

(R)-(+)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, salt withL-(−)-di-para-toluoyltartaric acid.

(I): X═F.A) N-Benzyl-2-(tetrahydro-2H-pyran-2-yloxy)-1-ethyl-amine maleate.

100 g of 2-(benzylamino)-1-ethanol are added at ambient temperature to amixture of 110 g of benzenesulfonic acid in 1.8 liters of DCM, thetemperature at the end of the addition being 34.4° C. and the pH=2. Thereaction mixture is cooled to 20° C. and 105 ml of 3,4-dihydro-2H-pyranare added dropwise, the reaction mixture turning yellow, then pink andfinally purple in color at the end of the addition. The mixture ispoured onto 2 liters of a 10% aqueous K₂CO₃ solution, then, afterseparating by settling, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated under vacuum. The oil obtained is dissolved in 200ml of AcOEt, a hot solution of 72.7 g of maleic acid in 655 ml of AcOEtis added and the mixture is left stirring overnight at ambienttemperature. The precipitate formed is filtered off, washed with 3×100ml of AcOEt and dried under vacuum at ambient temperature. 207 g of theexpected product are obtained in the maleate form.

Yield: 89%. ¹H NMR: δ (ppm): 1.2-1.7: m: 6H; 3.0: t: 2H; 3.1-3.8: m: 2H;4.1: s: 2H; 4.5: t: 1H; 7.2-7.4: m: 5H; 8.0: s: 1H.

B) 2-Chloro-1-(3,4-difluorophenyl)ethanone.

(X): X═F; Hal=Cl; process G, stage a).

The procedure is identical to that of stage A of example 1.C)2-{Benzyl[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-amino}-1-(3,4-difluorophenyl)-1-ethanone.

1.5 liters of a 10% aqueous K₂CO₃ solution are added to a suspension of200 g of the compound obtained in stage A in 1 liter of DCM and then,after separating by settling, the solvent is evaporated under vacuum andthe oil obtained is dissolved in 250 ml of THF. This solution is addedto a solution of 52.65 g of NaHCO₃ in 10.35 ml of water and the reactionmixture is heated to reflux. A solution of 108.55 g of the compoundobtained in stage B in 250 ml of THF is then added dropwise over 50minutes and the mixture is left stirring at reflux for 3 hours. Thewater is removed by azeotropic entrainment under a nitrogen atmospherewith simultaneous addition of 600 ml of THF over 2 hours. After coolingto ambient temperature, 4 angström molecular sieve is added to thesolution and the mixture is left stirring overnight. After filteringunder a nitrogen atmosphere, 800 ml of a solution of the expectedcompound in THF are obtained, which solution is used directly in thefollowing stage.

¹H NMR: δ (ppm): 1.4: m: 6H; 2.7: dt: 1H; 3.3: m: 2H; 3.6: m: 2H; 3.7:s: 2H; 4.0: s: 2H; 4.4: m: 2H; 7.0-7.4: m: 8H.D)1-{Benzyl[2-(tetrahydropyran-2-yloxy)ethyl]amino}−2-(3,4-difluorophenyl)but-3-en-2-ol.

The solution of the compound obtained in the preceding stage in THF isadded over 30 minutes under a nitrogen atmosphere, at a flow rate whichmakes it possible to obtain a bulk temperature of 55° C., to 911 ml of a1M solution of vinylmagnesium bromide (XI: Hal″=Br) in THF and then thereaction mixture is left stirring at 50° C. for two hours. The reactionmixture is hydrolyzed by running it onto 1.5 liters of a saturatedammonium chloride solution over 45 minutes while maintaining a bulktemperature of 30° C. 500 ml of water are added. After separating bysettling, the aqueous phase is extracted with 1 liter of diisopropylether, the organic phases are combined and the solvents are evaporatedunder vacuum. 241 g of the expected compound are obtained, which is usedwithout further treatment in the following stage.E) 1-[Benzyl(2-hydroxyethyl)amino]-2-(3,4-difluorophenyl)but-3-en-2-ol.

500 ml of MeOH are cooled to 5° C. and 57 ml of acetyl chloride areadded dropwise while maintaining a bulk temperature of 10° C. Thissolution is then added, over 1 hour at ambient temperature, to asolution of 241 g of the compound obtained in the preceding stage in 500ml of MeOH and the reaction mixture is left stirring for 2 hours atambient temperature. The reaction mixture is concentrated under vacuum,the oily residue is dissolved with 1 liter of water, the aqueous phaseis washed with 2×500 ml of diisopropyl ether, and the aqueous phase isbasified by addition of 40 g of NaOH pellets and extracted with 2×800 mlof toluene. 500 ml of water and 400 ml of toluene are added to theorganic phase and separation is carried out by settling. 2.083 liters ofa solution of the expected compound in toluene are obtained, whichsolution is used directly in the following stage (content by HPLC: 91mg/ml, i.e. a mass of 189.5 g of the compound (IVa): X═F)).F) 4-Benzyl-2-(3,4-difluorophenyl)-2-vinylmorpholine maleate.

6.4 g of benzyltriethylammonium chloride are added to the toluenesolution of the compound obtained in the preceding stage and then afreshly prepared and hot solution of 187 g of NaOH pellets in 187 ml ofwater is added, the bulk temperature being 50° C. 86 ml ofbenzenesulfonyl chloride are then added dropwise over 2 hours at a flowrate which makes it possible to maintain a bulk temperature of 55° C.maximum. After cooling to AT, 1 liter of water is added and the mixtureis left stirring for 15 minutes. After separating by settling, theorganic phase is washed with 2×1 liter of water and with 1 liter of asaturated NaCl solution. The organic phase is chromatographed on 180 gof silica and then the silica is rinsed with 400 ml of toluene. Thetoluene phases are combined and the solvent is concentrated undervacuum. 137.8 g of the expected compound are obtained in the free baseform.

A suspension of 50.7 g of maleic acid in 284 ml of AcOEt is heated toreflux, then a solution of 137.8 g of the free base compound obtainedabove in 62 ml of AcOEt is added and the mixture is left stirring for 12hours while allowing the temperature to return to AT. The mixture iscooled to 0° C. and left stirring for 1 hour, and the precipitate formedis filtered off, washed with 4×50 ml of cold AcOEt and dried undervacuum at AT. 157 g of the expected compound are obtained in the maleateform.

Yield: 60% calculated from the starting compound of stage C) of formula(X): X═F; Hal=Cl.G) 2-[4-Benzyl-2-(3,4-difluorophenyl)morpholin-2-yl]-1-ethanolhydrochloride.

500 ml of water are added to a suspension of 245.3 g of the compoundobtained in the preceding stage in 500 ml of toluene, and then 120 ml ofa 10N sodium hydroxide solution are run in. After separating bysettling, the aqueous phase is extracted with 500 ml of toluene, theorganic phases are combined and the water is removed by azeotropicentrainment at constant volume with addition of toluene. The toluenesolution is concentrated to a volume of 350 ml.

800 ml of a 0.5M solution of 9-borabicyclo-[3.3.1]nonane in THF areintroduced into a “pilot system” reactor placed under a nitrogenatmosphere and the solution is concentrated at atmospheric pressure to avolume of 400 ml. 600 ml of the 0.5M solution of 9-BBN in THF are againadded and the solution is reconcentrated to a volume of 700 ml of THF. Asolvent exchange is then carried out at constant volume by introductionof 700 ml of toluene, the bulk temperature changing from 68° C. to 110°C. The mass is cooled to 20° C. and precipitation of the dimer of 9-BBNis observed. The 350 ml solution of the compound (IIa): X═F, preparedabove is subsequently added and the mixture is left stirring for 8hours. The reaction mixture is cooled to 5° C. and 9.6 g oftetrabutylammonium hydrogensulfate and then 69 ml of 10N NaOH solutionare added. The bulk temperature preset value is adjusted to 20° C. and72.3 g of an 11M solution of hydrogen peroxide in water (33%, 130volumes, d=1.13) are added at a flow rate by mass of 1.2 g/min. The bulkpreset value is then adjusted to 35° C. and 72.3 g of the 11M hydrogenperoxide solution are added at a flow rate by mass of 1.8 g/min.Finally, the bulk preset value is adjusted to 50° C. and 72.3 g of the11M hydrogen peroxide solution are added at a flow rate by mass of 3g/min. The mixture is left stirring for 1 hour at 50° C., separation bysettling is carried out under warm conditions and 3 phases are obtained:toluene/cis-1,5-cyclooctanediol/water. The aqueous phase is removed, thetoluene phase is washed with 2×200 ml of water to remove the diol, thenthe organic phase is cooled to 20° C. and the organic phase is driedover Na2SO₄.95 ml of a 6.1M solution of HCl in ethanol are added to theorganic phase, initiation is carried out by addition of 1 g ofhydrochloride of the compound (IIIa: X═F) and the mixture is leftstirring at AT for 3 hours. The precipitate formed is filtered off,washed with 3×250 ml of toluene and dried under vacuum at AT. 164 g ofthe expected compound are obtained in the hydrochloride form.

Yield: 86%.

H) 2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, racemic.

(I): X═F; process A, stage b).

16 g of 50% wet 10% palladium-on-charcoal are introduced into ahydrogenation reactor placed under a nitrogen atmosphere and then asolution of 164 g of the compound obtained in the preceding stage in thehydrochloride form in 1.6 liters of NaOH is carefully poured in. Themixture is hydrogenated under a pressure of 3 bar at 40° C. for 3 hours.After cooling to AT, the catalyst is filtered off on a Whatman® filterpaper, the filter paper is washed with 100 ml of MeOH, 55 ml of 10N NaOHare added to the filtrate and the MeOH is concentrated under vacuum to avolume of 200 ml. A solvent exchange is carried out with water byazeotropic entrainment. After having removed all the MeOH, the mixtureis left stirring for 1 hour and the precipitate formed is filtered off,washed with 2×100 ml of water and dried under vacuum overnight at 40° C.102 g of the expected compound are obtained.

Yield: 94.8%.

I) (R)-(+)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, salt withL-(−)-di-para-toluoyltartaric acid.

(I): X═F; process A, stage c).

A suspension of 95 g of the compound obtained in the preceding stage in1.235 liters of MeOH is heated to 40° C. and a solution of 150.88 g ofL-(−)-di-para-toluoyltartaric acid in 475 ml of MeOH is added over 1hour. When half of this solution has been run in, initiation is carriedout by addition of 0.4 g of resolved salt and, when the solution hasfinished being run in, the mixture is left stirring for 4 hours 30minutes while allowing the temperature to return to AT. The mixture iscooled to 20° C. and stirring continued for 2 hours, and the precipitateformed is filtered off, washed with 2×100 ml of EtOH and dried undervacuum at AT. 100 g of the expected compound are obtained in the form ofthe salt with L-(−)-di-para-toluoyltartaric acid.

Yield: 40.8%. Final yield: 19.5%, calculated from the starting compoundof stage B) of formula (VIII): X═F. Enantiomeric purity: 97.4%(e.e.=94.8%).

EXAMPLE 4 Synthetic Route IV

(S)-(−)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol.

(I): X═F.

A) Methyl 2-phenylhexahydro-1H-pyrrolo[1,2-c]imidazole-3-carboxylate,single isomer (XVI).

a) (S)-1-[(Benzyloxy)carbonyl]proline.

This compound is commercially available.

b) Benzyl (S) −2- (anilinocarbonyl)-1-pyrrolidine-carboxylate.

9.7 ml of N-methylmorpholine are added under a nitrogen atmosphere to asolution of 20 g of the compound obtained in the preceding stage in 200ml of acetonitrile, this solution is then cooled to 0° C. and 7.7 ml ofethyl chloroformate are added over 45 minutes. The reaction medium iscooled to 0° C. and 7.3 ml of aniline are added over 45 minutes. Thereaction mixture is concentrated under vacuum, the oily residue isextracted with 200 ml of AcOEt, the organic phase is washed with 2×200ml of a pH=2 buffer solution, with 200 ml of water and with 2×200 ml ofa 10% aqueous NaHCO₃ solution, 200 ml of AcOEt are added to the organicphase, then the organic phase is dried over Na₂SO₄ and filtered, and thesolvent is concentrated under vacuum. The residue is taken up in 100 mlof tert-butyl methyl ether and the mixture is left stirring for 1 hour,and the precipitate formed is filtered off, washed with 20 ml oftert-butyl methyl ether and dried under vacuum at 40° C. 20.8 g of theexpected product are obtained.

Yield: 80%. ¹H NMR: δ (ppm): 1.8: m: 2H; 2.2: m: 2H; 3.5: m: 2H; 4.3:d.t: 1H; 4.9: d: 1H; 5.1: d: 1H; 7.0-7.4: m: 8H; 8.6: m: 2H; 10: d: 1H.

c) (S)-N-Phenyl-2-pyrrolidinecarboxamide.

A solution of 20 g of the compound obtained in the preceding stage and5.3 ml of concentrated HCl in 300 ml of MeOH is carefully poured under anitrogen atmosphere onto 2 g of 50% wet 10% palladium-on-charcoal andhydrogenation is carried out for 2 hours at atmospheric pressure and atAT. 5 ml of concentrated HCl are added, the catalyst is filtered off andthe filtrate is concentrated under vacuum. The residue is dissolved in200 ml of water, the aqueous phase is washed with 200 ml of AcOEt, theaqueous phase is basified by the addition of 5 g of NaOH pellets andextracted with 3×200 ml of DCM. The DCM is removed by azeotropicentrainment with THF and then the THF is evaporated under vacuum. 11.5 gof the expected product are obtained.

Yield: 94.5%. ¹H NMR: δ (ppm): 1.7: m: 2H; 2.0: m: 2H; 2.9: t: 2H; 3.3:s: 1H; 3.7: m: 1H; 7.1: d.d: 1H; 7.3: d.d: 1H; 7.7: d: 2H; 9.9: s: 1H.

d) (S)-N-(2-Pyrrolidinylmethyl)aniline.

80 ml of a 1M solution of lithium aluminum hydride in THF are heated toreflux under a nitrogen atmosphere and a solution of 12 g of thecompound obtained in the preceding stage in 120 ml of THF is slowlyadded. The reaction mixture is allowed to return to AT, 3 ml of water, 3ml of 10N NaOH and 9 ml of water are carefully added, and the mixture isleft stirring overnight at AT. The mixture is filtered and the filtrateis concentrated under vacuum. The oil obtained is distilled under vacuum(B.p.=158-164° C./1 mbar). 8.6 g of the expected product are obtained.

Yield: 76%. ¹H NMR: δ (ppm): 1.1: m: 2H; 1.6: m: 2H; 2.6-2.8: m: 4H;3.1: m: 1H; 5.3: t: 1H; 6.4: m: 3H; 7.0: m: 2H.

e) Methyl 2-phenylhexahydro-1H-pyrrolo[1,2-c]-imidazole-3-carboxylate,single isomer.

1.89 g of methyl hydroxymethoxyacetate are added to a solution of 2.64 gof the compound obtained in the preceding stage in 25 ml of toluene andthen the mixture is heated at reflux for 1 hour 30 minutes whileazeotropically removing the water formed. The reaction mixture isallowed to return to AT, 25 ml of water are added to dissolve theinsoluble materials, the organic phase is dried over MgSO₄ and thesolvent is evaporated under vacuum. 3.67 g of the expected product areobtained.

Yield: quantitative. ¹H NMR: δ (ppm): 1.4-2.0: m: 4H; 2.6: m: 1H; 3.1:m: 2H; 3.5: m: 1H; 3.6: s: 3H; 3.8: m: 1H; 4.8: s: 1H; 6.4: d.d: 2H;6.6: dd: 1H; 7.1: dd: 2H.

B)(3,4-Difluorophenyl)(2-phenylhexahydro-1H-pyrrolo[1,2-c]imidazol-3-yl)methanone,single isomer.

(XVII): X═F; process H, stage a).

A solution of 3,4-difluorophenylmagnesium bromide (XV: X═F; Hal′″=Br) isprepared from 0.85 g of magnesium turnings, 4 g of1-bromo-3,4-difluorobenzene and 20 ml of THF and this solution is storedat AT.

Furthermore, 0.13 ml of 1,2-dichloroethane is added under a nitrogenatmosphere to a mixture of 0.4 g of magnesium turnings in 20 ml of THFand the mixture is heated until it becomes cloudy and gaseous ethyleneis given off. 1.17 ml of 1,2-dichloroethane are then added in portionsof 0.13 ml and the mixture is heated at reflux for 1 hour. Thissuspension of anhydrous MgCl₂ thus obtained is allowed to return to AT,a solution of 3.67 g of the compound obtained in stage A) in 37 ml ofTHF is added, and the mixture is heated at reflux for 1 hour and isallowed to return to AT. This solution is then cooled to −70° C., 20.4ml of the solution of 3,4-difluorophenylmagnesium bromide prepared aboveare added while maintaining a bulk temperature of −70° C., and themixture is left stirring at −70° C. for 1 hour. The reaction mixture ispoured onto 30 ml of a saturated NH₄Cl solution and is left stirring for15 minutes. The THF is concentrated under vacuum, the residue is takenup in 50 ml of diisopropyl ether, the organic phase is washed with 30 mlof water and with 30 ml of a saturated NaCl solution and dried overMgSO₄, and the solvent is concentrated under vacuum. 4.59 g of theexpected product are obtained.

Yield: 85%.

C)1-(3,4-Difluorophenyl)-1-(2-phenylhexahydro-1H-pyrrolo[1,2-c]imidazol-3-yl)-2-propen-1-ol,single isomer.

(XVIII): X═F; process H, stage b).

A solution of 4.59 g of the compound obtained in the preceding stage in30 ml of THF is cooled to −70° C., 28 ml of a 1M solution ofvinylmagnesium bromide (XI: Hal″=Br) in THF are slowly added whilemaintaining a bulk temperature of −70° C., and the mixture is leftstirring at −70° C. for 1 hour. The reaction mixture is poured onto 30ml of a saturated NH₄Cl solution, the phases are separated by settlingand the solvent of the organic phase is concentrated under vacuum. Theresidue is extracted with 70 ml of diethyl ether, the organic phase iswashed with 30 ml of water and this organic phase is used directly inthe following stage.

D) 2-(3,4-Difluorophenyl)-2-hydroxybut-3-enal, single isomer.

(XIX): X═F; process H, stage c).

The ethereal solution obtained in the preceding stage is cooled to 5°C., 174 ml of 2% HCl are added and the mixture is left stirringovernight at 5° C. The organic phase is washed with 30 ml of water anddried over MgSO₄, and the solvent is concentrated under vacuum. 2.67 gof the expected product are obtained.

Yield: 96% (calculated from the starting compound of stage C of formula(XVII): X═F.E)(S)-(−)-1-[Benzyl(2-hydroxyethyl)amino]-2-(3,4-difluorophenyl)but-3-en-2-ol.

1.2 ml of 2-(benzylamino)-1-ethanol are added to a solution of 1.7 g ofthe compound obtained in the preceding stage in 34 ml of acetonitrile,followed by 3.63 g of sodium triacetoxyborohydride and 3 drops of aceticacid, and the mixture is left stirring for 1 hour at AT. The reactionmixture is hydrolyzed by addition of 50 ml of 1.2M HCl, the organicphase is concentrated under vacuum, the aqueous phase is washed with 50ml of diisopropyl ether, the aqueous phase is basified by addition of 7ml of 10N NaOH and extracted with 50 ml of diisopropyl ether, theorganic phase is washed with 2×50 ml of water and dried over MgSO₄, andthe solvent is evaporated under vacuum. 1 g of the expected product isobtained.

Yield: 35%. Enantiomeric purity: 99.4% (e.e.=98.8%).F) (S)-(−)-4-Benzyl-2-(3,4-difluorophenyl)-2-vinyl-morpholine.

0.04 g of benzyltriethylammonium chloride is added to a solution of 1.2g of the compound obtained in the preceding stage in 12 ml of tolueneand then a freshly prepared and hot solution of 2.34 g of NaOH pelletsin 2.4 ml of water is added, the temperature of the medium rising to 45°C. 0.55 ml of benzenesulfonyl chloride is then added while maintainingthe temperature at 50° C. After cooling to AT, 10 ml of water are addedand the mixture is left stirring for 1 hour. After separating bysettling, the organic phase is washed with 2×50 ml of water and driedover Na₂SO₄, and the solvent is evaporated under vacuum. The residue ischromatographed on 60 g of silica, elution being carried out with thecyclohexane/diethyl ether (90/10, v/v) mixture. 0.8 g of the expectedproduct is obtained.

Yield: 70%.G)(S)-(−)-(2-[4-Benzyl-2-(3,4-difluorophenyl)-morpholin-2-yl)-1-ethanol.

6 ml of a 0.5M solution of 9-borabicyclo-[3.3.1]nonane in THF are addedunder a nitrogen atmosphere to 0.8 g of the compound obtained in thepreceding stage, the bulk temperature is brought to 25° C. and themixture is left stirring for 24 hours. 6 ml of THF are added, thereaction mixture is cooled to 0° C., the addition is carried out, inportions of 5×0.2 ml, of a solution comprising 1 ml of an 11M solution(130 volumes) of hydrogen peroxide in water and 0.64 g of NaOH pellets,and the mixture is left stirring for 15 minutes at AT. The THF isconcentrated under vacuum, the mixture is extracted with 10 ml oftoluene, the organic phase is washed with 2×10 ml of water and driedover MgSO₄, and the solvent is evaporated under vacuum. The oil obtainedis chromatographed on 20 g of silica, elution being carried out with theDCM/diethyl ether (73/3, v/v) mixture. 0.78 g of the expected product isobtained.

Yield: 93%.

H) (S)-(−)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol.

(I): X═F; process A, stage b).

The addition is carried out under a nitrogen atmosphere, to 0.078 g of50% wet 10% palladium-on-charcoal, of a solution of 0.78 g of thecompound obtained in the preceding stage in 10 ml of MeOH and 0.195 mlof concentrated HCl. Hydrogenation is carried out for 2 hours atatmospheric pressure and at AT. The catalyst is filtered off and thefiltrate is concentrated under vacuum. 0.5 g of the expected product isobtained.

Yield: 85%. Enantiomeric purity: 99.95%.

EXAMPLE 5 Synthetic Route V

(S)-(−)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl)-1-ethanol.

(I): X═F.

A) 2-(3,4-Difluorophenyl)-2-hydroxybut-3-enal, single isomer.

This compound is prepared by using the procedures of stages A, B, C andD of EXAMPLE 4.

B) 2-(3,4-Difluorophenyl)but-3-ene-1,2-diol, single isomer.

(XX): X═F; process I, stage d).

A solution of 3.2 g of the compound obtained in the preceding stage in110 ml of toluene is cooled to 0° C. and a solution of 0.3 g of sodiumborohydride in 10 ml of EtOH is added dropwise. The reaction mixture ishydrolyzed with addition of 100 ml of a saturated NH₄Cl solution, theorganic phase, after separating by settling, is washed with 3×30 ml ofwater and dried over MgSO₄, and the solvent is evaporated under vacuum.The oily residue is chromatographed on silica gel, elution being carriedout with the DCM/diethyl ether (90/10, v/v) mixture. 1 g of the expectedproduct is obtained.

Yield: 31%.

C) 2-(3,4-Difluorophenyl)-2-vinyloxirane, single isomer.

(VII): X═F; process I, stage e).

A solution of 1 g of the compound obtained in the preceding stage and0.04 g of benzyltriethyl-ammonium chloride in 5 ml of DCM is added to asolution of 2 g of NaOH pellets in 2 ml of water and then 0.91 g ofbenzenesulfonyl chloride is run in at AT, the bulk temperature rising to35° C. 5 ml of DCM are added and the mixture is left stirring for 30minutes. The reaction mixture is hydrolyzed by addition of 20 ml ofwater and diluted with 20 ml of DCM. After separating by settling, theorganic phase is washed with 4×10 ml of water and dried over MgSO₄, andthe solvent is evaporated under vacuum. 0.91 g of the expected productis obtained.

Yield: quantitative.D)(S)-(−)-1-[Benzyl(2-hydroxyethyl)amino]-2-(3,4-difluorophenyl)but-3-en-2-ol.

0.742 g of 2-(benzylamino)-1-ethanol is added to a solution of 0.894 gof the compound obtained in the preceding stage in 4.5 ml ofacetonitrile and then the mixture is heated at reflux for 24 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upin 20 ml of toluene, and the organic phase is washed with 3×10 ml ofwater, acidified by addition of 20 ml of 0.5N HCl and extracted with 10ml of water. The acidic aqueous phase is washed with 10 ml of toluene,basified by addition of 0.41 g of NaOH pellets and extracted with 20 mlof toluene, the organic phase is washed with 3×10 ml of water and driedover MgSO₄, and the solvent is evaporated under vacuum. 0.99 g of theexpected product is obtained.

Yield: 60%. Enantiomeric purity: 98.8% (e.e.=97.6%).

E) (S)-(−)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol.

(I): X═F; process C and then process A, stages a) and b).

The preparation is carried out as in stages F, G and H of EXAMPLE 4,starting from the compound obtained in the preceding stage, and theexpected product is obtained.

EXAMPLE 6 Synthetic Route VI

(R)-(+)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, salt withL-(−)-di-para-toluoyltartaric acid.

(I): X═F.A) 4-Benzyl-2-(3,4-difluorophenyl)-2-vinylmorpholine maleate, (IIa),

This compound is prepared by using the procedures of stages A, B, C andD of example 1.B) Benzyl 2-(3,4-difluorophenyl)-2-vinylmorpholine-4-carboxylate.

A mixture of 41.98 g of the compound obtained in stage A in the freebase form (oil) and 0.55 g of K₂CO₃ is heated to 60° C., 28.68 g ofbenzyl chloroformate are then added dropwise over 25 minutes under anitrogen atmosphere, and the mixture is left stirring for 5 hours at 20°C. 100 ml of toluene and 70 ml of water are added to the still hotreaction mixture, then the organic phase, after separating by settling,is washed with water and dried over MgSO₄, and the solvent isconcentrated under vacuum. 64 g of the expected product are obtained,which product is used as is in the following stage.C) Benzyl2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)-morpholine-4-carboxylate.

A solution of 6.35 g of trimethylsilyl chloride in 8 ml of THF is addedunder a nitrogen atmosphere over 15 minutes to a mixture of 2.21 g ofsodium borohydride in 50 ml of THF and the mixture is left stirring atAT for 30 minutes. A solution of 7.17 g of the compound obtained in thepreceding stage in 11 ml of THF is subsequently added dropwise and themixture is left stirring at AT for 1 hour, then heated at reflux for 1hour and left stirring overnight while allowing the temperature toreturn to AT. 1.05 ml of water are carefully added dropwise to thereaction mixture and then the THF is concentrated under vacuum. Theresidue is taken up in 60 ml of toluene, 0.24 g of tetrabutylammoniumhydrogensulfate is added, 5.4 ml of 10N NaOH are then slowly added and,subsequently, 3.8 ml of an 11M solution of hydrogen peroxide in water(33%, 130 volumes, d=1.13) are added, the bulk temperature reaching 45°C. After stirring for 15 minutes, 60 ml of water are added to thereaction mixture, the organic phase, after separating by settling, iswashed twice with water (pH=7) and dried over MgSO₄, and the solvent isevaporated under vacuum. 4.83 g of the expected product are obtained,which product is used as is in the following stage.

D) 2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, racemic.

(I): X═F; process A, stage b).

A solution of 0.77 g of the compound obtained in the preceding stage in2.3 ml of toluene is added under a nitrogen atmosphere to 0.05 g of 50%wet 10% palladium-on-charcoal. Hydrogenation is carried out for 2 hours30 minutes at atmospheric pressure and at 40° C. After cooling to AT,water is added to the mixture, and the mixture is acidified by additionof 0.105 ml of concentrated HCl and filtered. After separating bysettling, the acidic aqueous phase is washed with toluene, basified byaddition of 0.141 ml of 10N NaOH and left stirring at AT for 1 hour. Theprecipitate formed is filtered off, washed with water and dried undervacuum at 60° C. 0.17 g of the expected product is obtained.

E) (R)-(+)-2-[2-(3,4-Difluorophenyl)morpholin-2-yl]-1-ethanol, salt withL-(−)-di-para-toluoyltartaric acid.

(I): X═F; process A, stage c).

The preparation is carried out as in stage G of EXAMPLE 1, starting fromthe compound obtained in the preceding stage, and the expected productis obtained.

1. A compound of formula:

in which X represents a halogen atom and R₁ represents an N-protectinggroup chosen from a benzyl group, a benzyloxycarbonyl group, a1-chloroethyloxycarbonyl group, a tert-butyloxycarbonyl group or anα-methylbenzyl group, in the racemic form, in the enantiomerically pureform or in the form of a mixture of diastereoisomers, and its optionalsalts with inorganic or organic acids.
 2. A compound of formula:

in which X represents a halogen atom and R₁ represents a benzyl group, atert-butyloxycarbonyl group or an a-methylbenzyl group, in the racemicform, in the enantiomerically pure form or in the form of a mixture ofdiastereoisomers, and its optional salts with inorganic or organicacids.
 3. A compound of formula:

in which X represents a halogen atom and Hal represents a halogen atom.4. The compound as claimed in claim 3 of formula (V), in which Halrepresents a chlorine or bromine atom.